Submissions for variant NM_000558.5(HBA1):c.43T>C (p.Trp15Arg)

dbSNP: rs33964317

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506883	SCV000601195	pathogenic	not provided	2020-12-29	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 6725558 (1984), 15008259 (2004)).
GeneDx	RCV000506883	SCV004169867	likely pathogenic	not provided	2023-05-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26659599, 26824843, 27830006, 6725558, 15008259, 22924376, 31553106, 26594346, 31304855, 19205971)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001078391	SCV004848826	pathogenic	alpha Thalassemia	2022-11-03	criteria provided, single submitter	clinical testing	The p.Trp15Arg variant in HBA1 (also known as HB Evanston) has been reported in several individuals with microcytosis (Honig 1984 PMID: 6725558, Harteveld 2004 MID: 15008259, https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=16). It has been reported in clinvar (Variation ID 439103) and was identified in 3/4792 South Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org/variant). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies using patient samples support an impact on protein function. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive alpha thalassemia. ACMG/AMP Criteria applied: PM2_supporting, PM3_Strong, PS3_Supporting.
Fulgent Genetics, Fulgent Genetics	RCV005018869	SCV005642329	likely pathogenic	Heinz body anemia; alpha Thalassemia; Hemoglobin H disease; Methemoglobinemia, alpha type; Erythrocytosis, familial, 7	2024-02-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506883	SCV005879057	likely pathogenic	not provided	2024-04-26	criteria provided, single submitter	clinical testing	The HBA1 c.43T>C; p.Trp15Arg variant (HB Evanston, also known as p.Trp14Arg when numbered from the mature protein, rs33964317, HbVar ID:16) has been reported in the compound heterozygous state in several individuals and families with phenotypes ranging from mild Hb H disease to microcytic anemia (Harteveld 2004, Honig 1984, Moo-Penn 1983, see HbVar and references therein). This variant is also reported in ClinVar (Variation ID: 439103), and is found in the general population with an overall allele frequency of 0.017% (28/166364 alleles) in the Genome Aggregation Database. The tryptophan at codon 15 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.705). Multiple functional assays show instability and skewed alpha/beta globin ratio when in-trans with other deletion alleles (Harteveld 2004 and Honig 1984). Based on available information, the p.Trp15Arg variant is considered to be likely pathogenic. References: Harteveld CL et al. A new Hb evanston allele [alpha14(A12)Trp --> Arg] found solely, and in the presence of common alpha-thalassemia deletions, in three independent Asian cases. Hemoglobin. 2004 Feb;28(1):1-5. PMID: 15008259. Honig GR et al. Hemoglobin Evanston (alpha 14 Trp----Arg). An unstable alpha-chain variant expressed as alpha-thalassemia. J Clin Invest. 1984 Jun;73(6):1740-9. PMID: 6725558. Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Moo-Penn WF et al. Hemoglobin Evanston: alpha 14(A12) Trp leads to Arg. A variant hemoglobin associated with alpha-thalassemia-2. Biochim Biophys Acta. 1983 Sep 14;747(1-2):65-70. PMID: 6882779.
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV001078391	SCV001244593	pathogenic	alpha Thalassemia	2019-11-25	no assertion criteria provided	curation